Background: Orphan Drug Programs are intended to promote research and therapeutic development for rare diseases by providing benefits such as enhanced regulatory guidance, financial incentives, and pathways for accelerated approval. Rare diseases are defined as diseases with a complete prevalence of <5 per 10,000 in the European Union – 27 countries (EU-27) or <200,000 people in the United States (US). There are between 7,000 and 10,000 different rare diseases affecting up to 60 million patients in the EU and US and potentially 400 million patients worldwide. Oncology indications have received the greatest number of orphan disease designations and approvals. However, changes in the prevalence of specific cancers over time may impact whether a disease meets the eligibility criteria for orphan designation. Objectives: This study aimed to identify examples of select cancers with a prevalence near the threshold of orphan disease designation in the EU-27 and US, describe prevalence trends in these cancers over time, and discuss implications for orphan designation and drug policy. Methods: Complete prevalence data were identified using publicly available sources for available cancer types. For the EU-27, complete prevalence by cancer type in 2010 and 2020 was extracted from the European Cancer Information System. For the US, complete prevalence of cancers was estimated using the US National Cancer Institute’s SEER program with ICD-O-3/WHO 2008 site recodes; age- and gender-specific limited-duration prevalence for 2000, 2010, and 2020 was calculated using the SEER*STAT software and then converted to complete prevalence with SEER’s ProjPrev and ComPrev softwares. Results: In the EU-27, cancers that would have met the orphan disease threshold in 2010 but not 2020 included: brain (2010: 3.94; 2020: 5.08 per 10,000) and small lymphocytic lymphoma/chronic lymphocytic leukemia (or CLL) (2010: 4.59; 2020: 6.04 per 10,000). Cancers close to the threshold in 2020 included multiple myeloma (4.32 per 10,000) and soft tissue (3.96 per 10,000). In the US, cancers that previously would have been considered orphan diseases that are now above the US threshold include CLL (2000: 88,678; 2020: 208,934), ovarian (2000: 183,068; 2020: 226,306), and Hodgkin lymphoma (2000: 128,994; 2020: 206,977). Conclusions: Monitoring cancer prevalence trends may help elucidate the impact of prevalence increases on future orphan drug designation and therapeutic development. Current orphan designation criteria do not account for population growth (US only), age distribution changes, or extended duration of disease/improved survival due to improved treatments; these definitions may inadvertently disincentivize new therapeutic development for rare disease patient populations with a prevalence near the threshold.